Watersoluble urea compounds containing heterocyclic nuclei in the molecule



Patented Feb. 21, 1933 UNITED STATES PATENT OFFICE OSKAR DRESSEL ANDANTON OSSENBECK, 0F COLOGNE-MULHEIM, AND ERNST TIETZE,

0F COLOGNE-ON-THE-RHINE, GERMANY, ASSIGNORS TO WINTHROP CHEMICAL COM-PANY, INC 01 NEW YORK, N. Y., A CORPORATION OF NEW YORK WATERSOLUBLEUREA COMPOUNDS CONTAINING HETEROCYCLIC NUOLEI IN THE MOLECULE NoDrawing. Application filed. November 30, 1929, Serial No. 410,871, andin Germany December 5, 1928.

The present invention relates to a process of preparing watcrsolublepharmaceutical substances being chemically urea compounds containinghcterocyclic nuclei in the molecule and to the new products obtainablethereby, more particularly it relates to compounds of the probablegeneral formula wherein Ar stands for a benzene or naphthalene nucleuscontaining at least one sultonic acid group, one as stands for aheterocylic nucleus attached to the adjacent nitrogen atoms by nuclearcarbon atoms, for example, tor the residue of acridine, quinazoline.quinoline, pyridine, pyrimidine and triazine, the other :1? stands for aheterocyclic nucleus attached to the adjacent nitrogen atoms by nuclearcarbon atoms. or for a -CO aryl-or sO -aryl-radical of the benzeneseries, such as benzoylor benzenesulfonyl, and 11 stands for an oxygenor a sulfur atom.

Our new products are obtainable by condensing in aqueous solution anaromatic amine of the benzene or naphthalene series containing at leastone sultonic acid group n water arid which may be otherwise substitutedwith a heterocyclic compound containing a replaceable halogen atom and anitro group. for example, a 4-chloro-6-nitro-quinazolinc, favorably inthe presence of an acid-binding agent, such as sodium acetate, or withan aroin'atic acid halogenide containing a nitro group, such asnitrobenzoylchloride or nitrobenzenesulfochloride, reducing the nitrogroup of the condensation product and again efiecting condensation inthe same manner with an aromatic acid halogcnide containing a nitrogroup in the nucleus in case the first condensation has been effectedwith a heterocycl ic compound, or with a heterocyclic nitro compoundcontaining a replaceable halogen atom, reducing the nitro group andtransforming the reduction product into the corresponding urea orthiourea according to one of the known methods, for example by means ofphosgene or thiophosgcne respectively.

Our new products are generally yellowish -crystalline substances,soluble in water and amine-4.6.8-trisulfonate are dissolved in water,.25kgs. of sodium acetate are added and the solution is heated to 5060 (J.kgs. of finely powdered G-nitro-i-chloroquinazoline are then added withstirring, which is continued until an acidified test portion no longerabsorbs nitrite. After filtering, the solution is reduced directly inthe customary manner with iron and acetic acid. It is then againfiltered, concentrated, if necessary by evaporation, acidified withhydrochloric acid and saturated with sodium chloride. The acid thenseparates slowly as a crystalline magma. The latter is filtered andredissolved to a neutral solution; 25 kgs. of sodium acetate are addedand after the addition of 20 kgs. of 3-nitro-4i-methyl-benzoylchloridestirring takes place at 20-30 C. until in an acidified test portion nofurther absorption of nitrite is observable. After filtering, thecondensation product is salted out with sodium chloride, filtered,reduced with iron and acetic acid and the amino-acid obtained isseparated from the reduction. liquid by means of hydrochloric acid andsodium chloride in the form of a crystalline magma.

For conversation into the urea the amino acid is dissolved to a neutralsolution in water, sodium acetate is added and phosgene is passed in at-40 C. until the ammo-acid is no longer detectable by the diazoreaction. During the passing in of the phosgene, the free acid evolvedis advantageously neutralized by the addition of alkali. The urea isprecipitated from the aqueous solution by means of alcohol as a darkyellow resin, which I afterslijviiigtorniszoyl-fZ-naphthylainine-fifi-trisiiltonic acid,

' which is filtered 'ind reduced in the custom- ;ir manner with iron andacetic acid. The ziniiiio coinp-ziiund, i'lissolvcii in outer. jviiliion pzissii'ig in pliosgene a normal urea. which I i iicTV-=11:iino-loiiinazolyl-1- is precipitated by the addition of alcoholin ohili visiininee-lite trisiilfonic acid, ohtainthe form of a resin.In its free form it has 80 ."iili {iiiicscrioed in Example 1. 1Sdissolved the following formula:

if HOzS t Q :11; l as NH- 1 N 'eiiti'al solution. legs. of Example4.i'\niline-3.5-disiilfonic acid is ended and Rtiiiliifl 15 thencondensed with ti-IlitI'O-l-ClllOiGQUiTiflZOllDO with 25 FJ-" asdescribed in example 1, reduced and conl 1 3 l mill dcnscd withinnitrohenzoylchloride. After l fl reduction of the nitro group phosgcncis in f f l troduced into the acetic acid solution until 1mm alreadydurmg the process the amino-group is no longer detectable bydiazotization. The urea formed is salted out with sodium chloride as ayellowishbrown powder. It has in its free state the following i saltedout with Sodium chloridei igzina ii: filtered and then reduced in 3.: Ymanner with iron and acetic formulm amino acid is separated from liquidwith hydrochloric acid 7 'W EH P1 '1 ,1 l N iiiii tnlUlMlL. the iteieid1111110- liti'i converted into the urea by treat- Q ll ;i; 1

' l. gili fene as described in Example H038 \N e gt-i'ecipitated fromtheaqueso H iiioii ;i E; yellow precipitate by the a 1 er ailColiOl.fimample 5.-On shaking a neutral aqueous l r l 'll C i i if NU/C\ l J-NH-- CO e i N 1 e 5 i 5 l w H I? V 1 Di k i 'cx ,1 N j,

. i eogii a )2 On shaking 1i. neiitriil aquesolution of'l-naphthyl;imine-4.6.8-sodium i=:i iii o: sodiuiii-3:2iiiinolienIioyl-Q- trisiilfonate to which sodium acetate has f" loeenedited with a benzene solution of tl-nitio fi-inetliyl-4-ehloroqninazoline, the o-nitro fl c niethvlquinazolyl-l-niiphthylziniine 4.6.8- oiicoiis oliition iviti'i the 11dtrisulfonic acid is obtained which is reduced in the known manner withiron and acetic acid. The reduction product is condensed withni-nitroheiizoylchloride, the nitro coninr qiiiiiitii oi illlil)-{)-Qhlq a( ri pound is reduced and the amino compound wilted ii:liciii zene, the reacti n gnaggr, transformed into the correspondingurea by 21 001": time to ii solid crystal introducing phosgene. The ureais salted ellil'iht -ii(Il(lyl3' -tli1llilObtTlout by the addition ofcommon salt and free state it has the following formula:

JK/ on; NH l l l 8 0 11 2 Example6.6-nitrobenzothiazolyl-EZ-naphthylamine-fi-disultonic acid is preparedby heating in an autoclave to about -110 C. about equimolecularquantities of 2- naphthylaxnine-AT-disodium sulfonate and (S nitro E2chlorobenzothiazole (compare British Specification No. 310,815) in thepresence of an acid-binding agent, for example sodium acetate. Thenitro-compound is reduced with iron and acetic acid and the aminocompound is condensed with m-nitrobenzoylchloride. After reduction ofthe nitro group the thiourea is formed by introducing into the aceticacid solution th-iophosgene until the amino group is no longerdotectable by diazotization. The thiourea is separated by the additionof common salt; it is a yellow powder, effective against bloodparasites.

Analogous compounds are obtainable by using other heterocycliccompounds, for example as are described in the Brit. Specifications255,811, 309,033 and 310,815.

It in Examples l5 phosgene is substituted by thiophosgene thecorresponding thioureas are obtainable which correspond to the ureas asregardsthe etliciency against blood parasites.

Ne claim:

1. As new products compounds of the probable general formula:

wherein Ar stands for a benzene or naphthalene nucleus containing atleast one sulfonic acid group as substitnent, one :1: stands for aheterocyclic nucleus attached to the adjacent nitrogen atoms by nuclearcarbon atoms, the other 0 stands .tor a residue of the group consistingof a heterocyclic nucleus attached to the adjacent nitrogen atoms bynuclear carbon atoms, and the groups -C()- aryland -SO -arylot thebenzene series, and y stands for one of the atoms oxygen and sulfur,being generally yellowish crystalline substances, soluble in water andbeing valuable pharmaceutical substances,

espe cially against blood parasites.

2. As new products compounds of the probable general formula:

soluble in water and being valuable pharmaceutical substances,especially against blood parasites.

3. As new products compounds of the probable general formula:

H03 NH- "1 NELCOQ l S i a Na --os wherein Ar stands for a benzene ornaphthalene nucleus containing at least one sultonic acid group assubstituent, one 0: stands for a heterocyclic nucleus attached to theadjacent nitrogen atoms by nuclear carbon atoms, the other so stands fora residue of the group consisting of a heterocyclic nucleus attached tothe adjacent nitrogen atom by nuclear carbon atoms, and the groups-CO-aryland -SO -arylof the benzene series, being generally yellowishcrystalline substances, soluble in water and being valuablepharmaceutical substances, especially against blood parasites.

4. As new products compounds of the probable general formula:

wherein Ar stands for a naphthalene nucleus being at least oncesubstituted by a sulfonic acid group, 02 stands for a heterocyclicnucleus attached to the adjacent nitrogen atoms by nuclear carbon atoms,m stands for one of the groups -CO-aryland -SO -arylof the benzeneseries, being generally yellowish crystalline substances, soluble'inwater and being valuable pharmaceutical substances, especially againstblood parasites.

5. As new products compounds of the probable general formula:

Ar.N"n.r.N'H.comma- 00 wherein m stands for a quinazoline nucleusattached with a carbon atom of the diazine nucleus to the nitrogen atomN" and with a carbon atom of the benzene nucleus to the nitrogen atom Nand R stands for a radical of the benzene series, being generallyyellowish crystalline substances, soluble in Water and being valuablepharmaceutical substances, especially against blood parasites.

As a new product the compound of the probable formula:

C if NILCO NH -oo H i \N/ OH:

being a yellow powder, effective against trypanosomcs, especiallyagainst trypanoso- 111a congolense.

In testimony whereof, we aliix 'our signatures.

OSKAR DRESSEL. ANTON OSSENBECK. ERNST TIETZE.

H018 NH

